title: Drosophila as a model for intractable epilepsy: gilgamesh suppresses seizures in para(bss1) heterozygote flies.
abstract: Intractable epilepsies, that is, seizure disorders that do not respond to currently available therapies, are difficult, often tragic, neurological disorders. Na(+) channelopathies have been implicated in some intractable epilepsies, including Dravet syndrome (Dravet 1978), but little progress has been forthcoming in therapeutics. Here we examine a Drosophila model for intractable epilepsy, the Na(+) channel gain-of-function mutant para(bss1) that resembles Dravet syndrome in some aspects (parker et al. 2011a). In particular, we identify second-site mutations that interact with para(bss1), seizure enhancers, and seizure suppressors. We describe one seizure-enhancer mutation named charlatan (chn). The chn gene normally encodes an Neuron-Restrictive Silencer Factor/RE1-Silencing Transcription factor transcriptional repressor of neuronal-specific genes. We identify a second-site seizure-suppressor mutation, gilgamesh (gish), that reduces the severity of several seizure-like phenotypes of para(bss1)/+ heterozygotes. The gish gene normally encodes the Drosophila ortholog of casein kinase CK1g3, a member of the CK1 family of serine-threonine kinases. We suggest that CK1g3 is an unexpected but promising new target for seizure therapeutics.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ich@berkeley.edu
authors.forename: Iris C
authors.initials: IC
authors.lastname: Howlett
authors.forename: Zeid M
authors.initials: ZM
authors.lastname: Rusan
authors.forename: Louise
authors.initials: L
authors.lastname: Parker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tanouye
mesh_terms: D000818:Animals; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics; D012640:Seizures / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D047389:Casein Kinase I; D029721:Drosophila Proteins; D012097:Repressor Proteins; D015222:Sodium Channels; D014157:Transcription Factors; D051153:Wnt Proteins; D051155:Wnt1 Protein; D000099229:RE1-Silencing Transcription Factor; C500129:chn protein, Drosophila; C469950:para protein, Drosophila; C074622:wg protein, Drosophila; C479663:gish protein, Drosophila
keywords: Drosophila; epilepsy; seizure-suppression; sodium channel